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Патент USA US3068233

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United States Patent O?tice
3,068,223
Patented Dec. 11, 1962
formula:
3,068,223
PHOSPHATE DERIVATIVES 0F STEROIDS
John P. Conhere, Barrington, KL, and Karl P?ster III,
West?eld, N..l., assignors to Merck & Co., Inc., Rahway,
N..l., a corporation of New Jersey
No Drawing. Original application Aug. 4, 1954, Ser. No.
447,912, now Patent No. 2,870,177, dated Jan. 20, 1959.
Divided and this application Nov. 18, 1958, Ser. No.
774,594
10
16 Claims. (Cl. 260-23955)
This invention relates to steroids and particularly to
phosphate derivatives of cortisone and hydrocortisone, to
processes for preparing them and to intermediate com
pounds thus obtained.
This application is a division of co-pending application
Serial No. 447,912, ?led August 4, 1954, now US. Pat
ent No. 2,870,177.
Since the discovery of the remarkable properties of
Red’
OH
or)
wherein R is an oxygen group (0:) thereby forming
an ll-keto steroid or a hydrogen and B-hydroxy group
(<1)
thereby forming an llls-hydroxy steroid; and salts there
of. These compounds are soluble in a large range of
solvents including water, and also maintain the same high
cortical activity as cortisone and hydrocortisone.
The compounds of this invention may be prepared
cortisone and hydrocortisone for use in the therapy of
arthritis and related diseases, there has been a wide
spread interest in ?nding other steroids and derivatives
of these compounds which not only possess the desirable
properties of these hormones, but also possess other de
sirable properties which would make them moie adapt
R-20-one (Compound I), wherein R is as de?ned above,
with an organic sulfonyl chloride compound to produce
able to a wider range of methods of administration.
the corresponding 3—ethylenedioxy-A?-pregnene-17:1,21
One
by reacting 3-ethylenedioxy-A5-pregnene~17a,2l-di0l-l l
of the most desirable properties which has been sought
diol-ll-R-20-one-2l-sulfonate compound (Compound II).
for hormones is water solubility. 'The advantages of 30 This compound is then treated with an iodide salt to form
having water soluble forms of cortisone and hydrocorti
the corresponding 2l-iodo pregnene (Compound III)
sone are readily apparent. As an example, the facile ad
which when reacted with an organic phosphate forms the
ministration of such hormones dissolved in a water so
corresponding 21-organic phosphate pregnene compound
lution allows almost instantaneous utilization of the hor 35 (Compound IV). This latter compound is then hydro‘
mones by the system. When the usual saline suspension
genated in the presence of a hydrogenation catalyst and a
of the acetate esters are injected, however, it required
tertiary amine to form the corresponding 2l-amine salt of
from 4 to 24 hours before such utilization occurs.
This
quick action would allow rapid alleviation of diseases
requiring hormone therapy.
One of the primary factors which has hindered the
search for water-soluble forms or derivatives of cortisone
and hydrocortisone is the particular characteristic of these
3 -ethylenedioxy - A5 -pregnene - l7a,2l -dio1 - ll - R
20-one-2l-phosphate (Compound V). This latter com
pound is hydrolyzed to produce the ZI-phosphate of cor
tisone or hydrocortisone (Compound VI) which may be
converted to a phosphate salt (Compound VII) by treat
ing with a basic substance.
As an alternate procedure the 3-ethylenedioXy-A5-preg
hormones in that many of their derivatives do not main
tain the necessary adrenal activity. This may be dem 4 GI nene - l7<x,21 - diol - l1 - R - 20 - keto - 21 - sulfonate
onstrated as for example in the case of cortisone sulfate
compound (Compound II) may be prepared by reacting
which exhibits little or no cortical activity.
_
cortisone or hydrocortisone (Compound VIII) with an
A primary object of the present invention is to produce
organic sulfonyl chloride compound to produce the corre
water-soluble derivatives of cortisone and hydrocorti 50 sponding A4-pregnene-17a,21-diol-11-R-3,20-dione-2l-sul
fonate compound (‘Compound IX) which is treated with
sone. A related object is to produce such derivatives
an ethylene dioxy yielding compound to form the corre
without any reduction in cortical activity. A further
spondin g 3-ethylenedioxy-A5-pregnene-17a,2 l-diol-l l-R
object is to provide processes for producing these deriv
20-keto-2l-sulfonate compound (Compound II). The
atives and intermediates useful in such processes. Other
A4 - pregnene - 170;,21 - diol - ll - R - 3,20 - dione - 21
objects and the advantages of the invention will appear
sulfonate compound (Compound IX) may be reacted
hereinafter.
with an iodide salt to form 2l-iodo-A4-pregnene-l7a-ol
The compounds which are the subject of the invention
1l-R-3,20-dione (Compound X) which is then treated
are phosphate derivatives of steroids having the general
with an organic phosphate to produce the corresponding
amazes
21-organic phosphate derivative (Compound XI). This
A
These reactions may be chemically represented as fol
lattcr compound is reacted with an ethylene dioxy yielding compound to produce the corresponding 3-ethy1enedi~
lows wherein R is as de?ned above, R2 is an alkyl group,
R3 is an aryl group, R4 is a tertiary amine and Y is a
Oxy-M-compound (Compound IV).
metal group and n is a Whole integer varying from 1 to 2.
Compound VIII
0:
0
CHQOH
GHQ-0802B?
C:
C=O
I "OH’
I "OH
Compound I
Compound IX
\
[/
O
0
l
_
a
l
C‘H'QO—SO:Ra
(‘T/Hal
=0
'
O=O
vI--OH
I---o15r
Rm
RCAO
Compound III,
Compound X
0
l
(IJHZI
(‘Ergo-1N0 CHzR?):
(13:0
“OH
C=O
I ——OH
R
R
0
Compound III
\
/
/1
Compound XI
-
O_
_
O
c
l
O
0
Compound IV
3,068,223
Compound V
0
'r/
on
o
l/
ore-01x
=0
OY
CH2-O P\
on
o=o
I --OH
OY
| --OH
3:
Compound VI
()=
-—->
Compound VII
0:
The 3-ethylenedioxy-M-pregnene - 17a,21-diol—11-R-20
one, where R is as de?ned above, is reacted with an or~
oxy-M-pregnene-l7a,21-diol-1l-R-ZO-one is converted to
a 21-tertiary amine salt of the 2l-phosphate compound
ganic sulfonyl chloride to produce the corresponding 21
sulfonoxy-pregnene compound. The sulfonyl chloride is
of the formula R2SO2Cl wherein R2 is an alkyl group
by treating with a tertiary amine (R4) and hydrogenating ,
Suitable
35 in the presence of a hydrogenation catalyst.
tertiary amines are N-methyl morpholine, N-methyl pi
peridine, dimethylaniline, diethylaniline and trimethyl
preferably having a carbon chain length of from one to
six carbon atoms. Typical examples of such groups are
amine. The hydrogenation catalyst may be any of the
conventional catalysts such as platinum, nickel or pal
ladium and oxides of these metals. The catalyst may be
methyl, ethyl and propyl. The reaction is preferably car
ried out in a solvent such as pyridine or other tertiary
amines. The reaction is usually complete in about 1 to
3 hours when the temperature is maintained at approxi
mately 0° C. The product is recovered by diluting the
reaction mixture With Water and recovering the crystalline
material.
supported on a suitable carrier such as barium sulfate,
calcium carbonate, barium carbonate and the like. The
reaction is preferably carried out in a solvent such as an
2. Ci
The ZI-sulfonyl derivative of the 3-ethylenedioXy-A5- I
pregnene-17m,2l-diol-1i-R-ZO-one is converted to the cor—
responding 21-iodo compound by treating with an iodide
salt. The reaction is conveniently effected by contacting
alcohol as for example ethanol, methanol or propanol.
The reaction is carried out at approximately 0° to 166°
(3., preferably at room temperature, until two mols of
hydrogen are taken up. The product is separated from
the reaction mixture by any of the conventional means
such as diluting with Water, removing the impurities by
the reactants in a solvent such as an alcohol, ketone or Gt)
extracting with a solvent and concentrating the water
ether.
Typical examples of suitable solvents are meth~
anol, ethanol, propanol, methyl butyl ether, ethyl ether,
acetone and methyl ethyl ketone. The reaction is pref
erably carried out at a temperature of approximately 25°
to 100° C. and is usually complete in 1/2 to 2 hours. ,-r
The product may be separated from the reaction mixture
by the addition of a non-solvent such as Water.
The ethylenedioxy-2l-iodo-nipregnene-17a-0l-1 1-11-20
one is converted to the corresponding Zl-organic phos
solution to dryness.
The 3-ethylenedioxy group of the ZI-amine salt is hy
drolyzed to form the 2l-phosphate of cortisone or hydro
cortisone. The hydrolysis may be carried out by treating
with a strong acid in a suitable solvent such as acetone,
methanol, ethanol, benzene or toluene. Strong acids such
as hydrochloric acid, sulfuric acid, perchloric acid and
p-toluene sulfonic acid, used in dilute concentrations, are
e?ective for the hydrolysis. The reaction may be car
phate compound by treating with an organic phosphate. 60
ried out from about 20 to 100° C. but is conveniently
The organic phosphate is of the formula
effected at the re?ux temperature. The reaction is ordi
narily complete in from several minutes to 1 hour. A
‘preferred procedure for the hydrolysis is to contact a
wherein R3 is an aryl group having a six carbon ring.
Examples of such groups are phenyl and substituted
solvent solution of the 21-amine salt with an anion ex
phenyls. The organic phosphate is preferably used in the
those shown in US. Patents 2,597,494; 2,597,440;
2,570,822; 2,567,836 and 2,543,666. Trade names of
form of a salt such as the silver, sodium, potassium,
barium or calcium salt or other metal salts Which form
insoluble iodides.
The reaction is conveniently carried
out in the solvent for the reactants such as benzene, tolu
ene, xylene or dioxane and at the re?ux temperature of
the solvent. The reaction usually requires from 4 to 26
hours for completion. The product may be recovered
by the addition of a non-solvent such as an ether.
change resin on the hydrogen cycle. Suitable resins are
speci?c resins are Amherlite Iii-105, Ainberlite Iii-120
and Amberlite Ill-100 (produced by Rollin & Haas Co).
The phosphate derivatives of cortisone and hydrocor
tisone may also be prepared directly from cortisone and
hydrocortisone by reacting with an organic sulfonyl chlo
ride compound to produce the corresponding M-pregnene
l7a,21-diol-li-R-3,20-dione 2l-sulfonate compound. The
The 21-organic phosphate compound of 3-ethylenedi 75 sulfonyl chloride is of the formula RZSG2SI wherein R2
3,068,223
?
is as de?ned above. The reaction is preferably carried
out in a solvent such as pyridine, benzene, toluene, tetra
hyd'rofuran or dioxane. The reaction is carried out most
effectively at approximately 0° C. and at this temperature
the reaction is complete in l to 3 hours. The product is
recovered by diluting the reaction mixture with water and
recovering the crystalline material.
'
The A‘i-pregnene-17a-2l-diol-l1-R-3,20-dione 2l-sulfo
8
by the addition of a non-solvent to precipitate the salt.
Typical examples of salts which may be formed are
sodium, calcium, potassium, magnesium, barium, am
monium and the like. By controlling the amount of
reactants both. the mono and di salts may be formed.
Table I demonstrates the activity of the 21-phosphates
The data is the result of one day liver glycogen tests in
mice by oral administration.
nate compound may then be converted to the correspond
ing 3-ethylenedioxy derivatives. This reaction is con
Table I
veniently achieved by reacting with ethylene glycol in
the presence of an acid catalyst or by an exchange reac
tion with an ethylenedioxy yielding compound such as
an ethylenedioxy derivative of a lower aliphatic ketone
such as acetone, methyl ethyl ketone, mesityl oxide and the
like. If desired, this reaction may be effected in an inert
solvent such as benzene, toluene, xylene, tetrahydrofuran
or dioxane. The reaction proceeds rapidly at an elevated
Liver Glycogen
Dose (y/lO
(mg/l0 gm.
gm. mouse) mouseiStand—
ard Error)
Substance
None ________________________________________________ _.
Cortisoue Acetate _____________ ._
2O
Sodium Cortisone Phosphate ___________ __
20
6 litt39
8 610.52v
8 11071
temperature, as for example at the re?ux temperature in
Table II shows the results from groups of 8 mice re
from 1 to 5 hours. Ordinarily a small amount of a strong 20 ceiving 5 hourly doses of the phosphate or free alcohol,
subcutaneously or orally. The total dose was 40 'y of
acid such as p-toluene sulfonic acid or sulfuric acid is add
ed to enhance the rate of the reaction. Following the com
cortisone alcohol per 10 gm. weight of the mouse, or its
pletion of the reaction the acid is neutralized with a
molecular equivalent of the phosphate.
base, the mixture is diluted with water and the desired
Table II
product is extracted from the mixture with an immiscible ~
solvent. The product may be isolated by removing the
solvent by evaporation under reduced pressure.
Substance
Route
153?}
mouse+S.G.)
The M-pregnene-17a,21-diol~ll-R-3,20-dione 2l-sul
fonate compound may be converted to the corresponding
2l-iodo compound by reacting with a suitable iodide salt. 30
None _______________________ _.
Cortlsone Alcohol. ____
9. 410. 56‘
Ordinarily it is preferred to effect the reaction with an
Cortisone Phosphate
9. 8;t;0. 74
4. 3:1;0. 15
alkali metal salt such as sodium iodide in a solvent such
as acetone or an alcohol. The reaction proceeds at ordi‘
Cortisone Alcohol. __
11. 71:0. 44
Cortisone Phosphate
10. 510. 63
nary temperature in usually less than one hour. The prod
The following examples illustrate vmethods of carrying
uct ‘may be recovered by adding water to the mixture, 35 out the present invention, but it is to be understood that
extracting the product and evaporating the solvent.
The 2l-iodo-A4-pregnene—l7ot—ol-ltl-R'-3,20—dione maybe
reacted with an organic phosphate to form the corre
sponding 21-organic phosphate compound. The organic
phosphate is of the formula (TUCH?hPC-(OH) wherein
R3 is as de?ned above. The phosphate is usually used in
the form of a salt as for example the silver salt or other
metal salts which form insoluble iodides. The reaction
is preferably carried out in a solvent such as benzene,
toluene, tetrahydrofuran or dioxane. The reaction pro
ceeds favorably at the re?ux temperature of the solvent.
The reaction usually requires from 4 to 20 hours for com
these examples are given for purposes of illustration and
not of limitation.
EXAMPLE 1
3-Etheylcnedioxy-M-Pregnene-l 7a,21-Di0l-11,20-Dione
A 4.72 g. sample of 3-ethylenedioxy-A5-pregnene~
17u,21-diol-1l,20-dione 21-acetate is suspended in 260 ml.
of methanol and the reaction mixture purged four times
with nitrogen. Sodium methoxide (0.675 g.) is added
and the stirred suspension heated to 60° C. under nitro
gen. After ?ve to seven minutes the solution is clear. The
heating is continued for an additional ?ve minutes and
pletion. The product may be precipitated by the addition
the reaction mixture cooled to 15° C. Glacial acetic acid
of a non-polar solvent such as petroleum ether.
(0.84 ml.) and 100 ml. of water are added and the re
The 21-phosphate derivative of the A4-pregnene-17m,21 50 action mixture concentrated under vacuum to 250 ml.
diol-11-R-3,20-dione may then be converted to the cor
An additional '100 ml. of water is added and the concen
responding A5-3-ethylenedioxy compound. This reaction
tration continued to a volume of 200 ml. The slurry is
is conveniently achieved by reaction with ethylene glycol
cooled and the solid collected and dried to yield 4.0 g. of
in the presence of an acid catalyst or by an exchange re
product, MP. 178-185" C. Recrystallization from ethyl
action with an ethylenedioxy yielding compound such
acetate-petroleum ether gives 2.6 g., M.P. 198~200° C.
as an ethylenedioxy derivative of a lower aliphatic ketone
Ultraviolet absorption spectra shows 13% of 4.4 at 2920
such as ketone, methyl ethyl ketone', mesityl oxide and
the like. ‘If desired, this reaction may be effected in an
inert solvent such as benzene toluene, tetrahydrofuran or
dioxane. The reaction proceeds rapidly at elevated tem- -.
peratures. As for example, at the re?ux temperature the
reaction is complete in l to 5 hours. ?rdinarily a small
amount of strong acid such as p-toluene sulfonic acid
or sulfuric acid is added to enhance the rate of reaction.
Following completion of the reaction the acid is neutral
A. Calc’d for C23H32O6 (404.49): C, 68:29; H, 7.97.
Found: C, 68.03; H, 8.26.
EXAMPLE 2
3 -E thylen ed1' oxy-M-Pregnene-J 7OL,21 -Di0l-1 1 ,ZO-Dione
21 —Methane-Sulf0nate
A 1.0 g. sample of 3-ethylenedioxy-A5-pregene-1711,21
diol-ll,20-dione in 8 m1. of pyridene is cooled to 0° C.
and treated with 4 ml. of methanesulfonyl chloride. After
standing for two and one—half hours at 0° C., the reaction
mixture is poured into 150 ml. of cold water and aged
in an ice bath. The crystals are‘ collected and washed
with water. The solid is triturated with methanol and
70
ether to give 850 mg. of solid, M.P. ISO-182° C. dec.
The salts of the 21-phosphate derivative or cortisone
ized with a base, the mixture is diluted with water and
the desired product is extracted from the mixture with
an immiscible solvent. The product may be isolated by
removing the solvent by evaporation under reduced pres
sure.
.
and hydrocortisone may be prepared by reacting the
Recrystallization from acetonitrile-ether yields 570 mg,
compound with an aqueous solution of alkali or alkaline
earth bases or salts such as hydroxides, carbonates, bi
carbonates or acetates. The product may be recovered
2380 A. Calc’d. for CHI-13.1088: C, 59.73; H, 7.10; S,
6.64. Found: C, 59.85; H, 6.89; S‘, 6.75.
MP. 20l—202° C.
The material has no absorption at
9.
stream
EXAMPLE 3
trione 21-methane sulfonate in 30 ml. of acetone is treated
Sulfonate
with 220 mg. of sodium iodide. After re?uxing for 10
minutes, the mixture is ?ltered and the ?ltrate concen
trated to 20 ml. Water (50 ml.) is added, the mixture
M-Pregrzene-J7a,21-Diol-3,11,20-Tri0ne ZJ-Methane
Cortisone (6.0 g.) is dissolved in 40 ml. of pyridine,
cooled and the crystals collected and washed with Water
cooled to 0° C., and treated with 1.6 ml. of methane
and dried to give 420 mg. of product; dec. 160-175 ° C.
sulfonyl chloride. After standing for one-half hour at
0° C. the reaction mixture is poured into 400 ml. of
Recrystallization from acetone-petroleum ether gives
crystals dec. 170°-175° C. Calc’d: I, 26.98. Found:
I, 26.72.
EXAMPLE 8
to give 6.6 g. of product, M.P. 122-124° C. Recrystal 10
lization from methanol yields either of two dimorphic
d’l-Pregnene-l7a,21-Di0l-3,11,ZO-Ttione
forms; M.P. 124-125° C. or M.P. 195-196” C. dec.
21 -Dibenzylph0sphaze
water and the aqueous suspension aged in an ice bath.
The crystals are collected, washed with water and dried
Calc’d. for C22H30O7S: C, 60.25; H, 6.90; S, 7.31. Found:
C, 60.25; H, 7.09; S, 7.61.
A 1.6 g. sample of 2l-iodo-M-pregnene-ll7ot-ol~3,11,20
trione and 1.45 g. of silver dibenzylphosphate are sus
pended in 150 ml. of benzene and 25 ml. of solvent dis
tilled therefrom to dry the system. The mixture is re
EXAMPLE 4
3-Ethy[enediOxy-AE-Pregnene-J 7 0:,21 ~Di0l~1 1 ,ZO-Dione
21 -Methane Sulfonale
?uxed for sixteen hours and ?ltered while hot. The resi
A 1.0 g. sample of M-pregnene-l7ot,2l-diol-3,11,20-tri 20 due is washed with Warm benzene and the combined ?l
trates concentrated to a syrup which crystallized. The
one 21-methane sulfonate, 50 mg. of p-toluenesulfonic
syrup is crystallized from benzene-petroleum ether mix
acid hydrate, 10 ml. of the dioxolane of mesityl oxide and
ture to give 1.9 g. of product, M.P. 147-149" C.
50 ml. of benzene are re?uxed for four hours. The re
A
portion recrystallized from acetone-petroleum ether, M.P.
160-162° C. Calc’d. for C35H41O8P: P, 4.99. Found:
action mixture is cooled, Washed with sodium bicarbonate
solution and then with water. After drying over mag
nesium sulfate the solution is concentrated to a syrup and
P. 4.68.
taken up in ethyl acetate. The slow addition of petroleum
ether precipitates crystals, M.P. 168-175 ° C. Recrystal
EXAMPLE 9
3 -E thylenedioxy-M-Pregnene-l 701,21 -Di0l-11 ,ZO-Dione
21 -Dibenzylph0s.phate
lization from ethyl acetate yields 150 mg. of substantially
pure 3-ethylenedioxy-M-pregnene-17a,21-diol-11,20-dione
ZI-methane sulfonate.
EXAMPLE 5
A 1.0 g. sample of A4-pregnene-17a,2l-diol-3,l1,20
trione 2l-dibenzylphosphate, 0.1 g. of p-toluenesulfonic
acid monohydrate, 3.5 ml. of the dioxolane of mesityl
3-Ethylenedioxy-21 -I0do-A5-Pregnene-1 7a-Ol-1 1,20-Di0ne
oxide and 100 ml. of benzene are re?uxed for 6 hours and
A 570 mg. sample of 3-ethylenedioxy-A5-pregnene 35 the Water collected in a Dean-Stark trap. The solution is
17u,2l~diol-ll-,20-dione ZI-methane sulfonate, 280 mg.
cooled, washed with aqueous sodium bicarbonate, and
of sodium iodide and 35 ml. of ethanol are re?uxed for
one-half an hour. The mixture is ?ltered and the ?ltrate
concentrated to 25 ml. Water (30 ml.) is added and the
mixture concentrated to 50 ml. The solid is collected,
washed with Water and dried to give 510 mg. of product,
Water, and then dried over magnesium sulfate. The or
ganic layer is concentrated to a syrup which is crystallized
from benzene-petroleum ether to give rystals MP. 75-83°
C.
Chromatographic separation over “?orisil,” yields a
crystalline crop, MP. 65-75 ° C. which is a different modi
?cation of the compound formed in Example 6.
dec. 123° C. Calc’d. for C23H31IO5: C, 53.70; H, 6.08.
Found: C, 53.81; H, 5.80.
‘
EXAMPLE 6
45
3-Ethylenea'ioxy-A5-Pregnene-J 7 (1,21 ~Di0l-1 l ,ZO-Dione
21 -Dibenzylph0sphate
EXAMPLE l0
M-Pregnerze-I704,21-Di0l-3,11,20-Tri0ne 21 -Ph0spl2ate
1.0 g. of 3-ethylenedioxy-M-pregnene-l70¢,2l-diol-l1,20
dione 2l-dibenzylphosphate is dissolved in 100 ml. of
A suspension of 3.63 gm. of 3-ethylenedioxy-21-iodo
ethanol containing 4 m1. of N-methylmorpholine and hy
A5-pregnene-17ot,-ol-11,20-dione and 3.2 gm. of silver di
benzylphosphate in 534 ml. of benzene was concentrated 50 drogenated at room temperature and atmospheric pres
sure in the presence of 1.0 g. of palladium oxide which
has been prereduced. The reaction mixture is ?ltered and
at atmospheric pressure to a volume of approximately
321 ml. (213 ml. of benzene distilled). The resultant
slurry was refluxed for 20 hours, with protection from
concentrated in vacuo to a syrup. The syrup is dissolved
in water and extracted with ethyl acetate and then ether.
moisture. The mixture was ?ltered while hot and evapo
rated in vacuo to a volume of 50 m1., and ?ltered again. 55 The aqueous layer is concentrated to dryness to give 820
mg. of solid N-methylrnorpholine salt of 3-ethylenedioxy
By keeping the solution hot while adding (heptane)
Skellysolve “b,” crystals of 3-ethylenedioxy-A5-pregnene
l7oc,21-dlOl-l1,20-di0n6 2l-dibenzylphosphate formed.
a5~pregnene - 17:4,21 ~ diol-11,20-dione 21-phosphate.
A
360 mg. sample of this solid in 20 ml. of methanol is
shaken overnight with 640 mg. of methanol dried Amber
If the mixture was allowed to cool before complete
crystallization had occurred the gelatinous form of the 60 lite IP-120 (ion exchange resin) on the hydrogen cycle.
The resin is removed and the supernatant layer contained
product would appear in the supernatant. Reheating and
cortisone phosphate which is separated from the methanol.
keeping hot during the crystallization period afforded all
crystalline material. The crystals were collected, Washed
EXAMPLE 1 1
with ethyl ether and air dried. The product, 3-ethylene
Sodium Salt 0]‘ M-Pregnene-l 7a,21-Di0l~3,l1 ,ZO-Triorte
21 ~Plz0sphate
dioxy ~ A5 - pregnene-l7e,21-diol-11,20-dione 21-dibenzyl
phosphate, was redissolved and treated with Darco G-60,
reprecipitation of the product as above resulted in 1.98
gm. of crystalline material, M.P. 150-151.5” C. Calc’d.
The cortisone phosphate is treated with 45 mg. of
sodium bicarbonate in 2 ml. of water. The Whole is con
for C3qH45O9P: C, 66.85; H, 6.82; P, 4.66. Found: C,
70 centrated to dryness and the residue taken up in water
67.00; H, 6.64; P, 4.56.
and shaken out with ethyl acetate. The aqueous layer
is concentrated to dryness, dissolved in methanol and 1:1
absolute ether-ethanol added to precipitate sodium cor
tisone phosphate. x max. 238, 13% 290, [a]D25+l45°
EXAMPLE 7
21 Jodo-M-Pregnene-J 7oc-Ol-3,11,20-Tri0ne
‘ A 500 mg. sample of A4-pregnene-17u,2l-diol~3,11,20
75
(c.=.l, methanol).
3,068,223
11
12
A5-pregnene-17a,21,di0l-11,20-dione in 200 ml. of dry
EXAMPLE 12
pyridine is cooled to 0° C. and treated with 7.5 ml. (0.1
-A4-Pregn'ene-1 1 [ii 7 (1,21 -l"riol-5' ,ZO-Dioue 21 ~Phospimle
mol) of methanesulfonyl chloride. After standing 21/2
The compound a‘l-pregnene-l1,8,l7u,21-triol-3,20-dione
'2l-phosphate is prepared by the procedure of Examples
1 to 10 by using 3-ethylenedioxy-M-pregnene-115,111,21
triol-ZO-one and M-pregnene-lldlhll-triol-3,20-dione
hours at 0° C., the reaction mixture is poured into 8.5
liters of cold water and aged for a half-hour in an ice
bath. The crystals are collected and washed with water,
methanol, and ?nally ether. Recrystallization from aceto
nitrile-ether yields 21 g. of 3-ethylenedioxy»A5-pregnene
respectively as the starting material in Examples 1 and 3.
17a,21,21-diol-11,20-dione ZI-methanesulfonate, M.P.
EXAMPLE 13
201-202° C.
Potassium salt of A4-Pregnene-J7ot,21-Di0i-3,1LZO-Trione
EXAMPLE 19
2] -Ph osphate
A methanol solution of A‘t-pregnene-17a,2l-diol-3,ll,
20~trione 21-phosphate is treated with two equivalents
3-Ethylenedioxy-21 Judo-M-Pregnene-l 7a
Ol-11,20-Dione
of potassium bicarbonate in the same manner as described 15
for the sodium salt in Example 11. The mono-salt is
prepared by treating with one equivalent of potassium
bicarbonate.
EXAMPLE 14
Ammonium Salt of M-Pregneue-l 7a,21-Di0l-3,I1,20
T rione 21 -Plz0sphate
A solution of a‘i-pregnene-17a,21-diol-3,11,20-trione
A suspension of 13.5 g. of 3-ethy1enedioxy-A5-pregnene
17a,21—diOl-11,20—di011€ ZI-methanesulfonate and 6.7 g.
of sodium iodide in 830 ml. of ethanol is boiled for a half
hour under re?ux. The mixture is ?ltered while hot,
then evaporated in vacuo to about 450 ml. It is then
20 diluted with a liter of water, and further evaporated to
about one liter ?nal volume. The resultant slurry is
cooled to 0° C., and the crystals are collected, washed
with water, and air dried. Yield, 13.5 g‘. of 3-ethylene
2l-phosphate is treated with two equivalents of dilute am
dioxy - 21
monium hydroxide solution to form the diammonium salt. 25 123° C.
- iodo - A5 - pregnene-17u-ol-l1,20 - dione,
The mono-salt is prepared by treating with one equivalent
dec.
EXAMPLE 20
of ammonium hydroxide. The product was separated as
3-Ethylenedioxy-M-Pregneue-I 70;,21-Di0l-1 1 ,ZO-Dione
in Example 11.
21 -Dibenzylph0sphate
EXAMPLE 15
Sodium Salt of M-Preguene-Ildl7u,21-Tri0i-3,20-Dioue
21 -Ph0sphate
A solution of A4-pregnene-1l?,17a,21-triol-3,20-dione
30
A suspension of 13.5 g. 3-ethylenedioxy-21-iodo-A5
pregnene-17a-ol-11,20-dione and 12 g. of silver dibenzyl
phosphate [prepared as described in Sheehan, J. Am.
21~phosphate is treated with two equivalents of sodium
‘Chem. Soc. 72, 1312 (1950)] in 2 liters of benzene is
bicarbonate. The mono-sodium salt is prepared by treat 35 evaporated (atmospheric pressure) to 1.2 liters volume,
ing with one equivalent of bicarbonate. The product is
and then boiled under re?ux for 20 hours, with protec
tion from moisture. The mixture is ?ltered while hot,
separated as in Example 11.
evaporated to 200 ml., ?ltered again, and then diluted
EXAMPLE 16
with petroleum ether to a slight turbidity. The mixture
Potassium Salt of M-Pregneue-II?J 7a,21-Tri0l-3,20
410 is cooled ‘to 0° C., and the crystals of 3-ethylenedioxy-N
Dione 21 -Ph0sphate
pregnene - 17a,21 - diol-l1,20-dione 2l-dibenzylphosphate
which precipitated are collected, washed well with ether,
A solution of A4~pregnene-1l?,17u,21-triol-3,20-dione
and air dried. Yield 13.4 g., M.P. 70°~75° C.
21-phosphate is treated with two equivalents of potassium
bicarbonate to form the dipotassium salt.
The mono
potassiurn salt is prepared by treating with one equivalent 45
of potassium bicarbonate. The product is separated as
in Example 11.
EXAMPLE 17
EXAMPLE 21
3-Ethylen edi0xy-A5-Pregnene-1 7a,21~Di0l-I1,20-Di0ne
21 -Phosphate, N—methylm0rpholine Salt
A suspension of 5.0 g. of palladium oxide (PdO) in
500 ml. of absolute ethanol and 10 ml. of N-methylmor
3-Ethylenedi0xy-A5-Pregnene-17a,21-Di0l-11,20-Di0ne
A suspension of 4.72 g. (10.6 millimols) of 3-ethylene
dioxy-A5-pregnene-17a,2l-diol-l1,20-dione 21-acetate in
pholine is reduced at 40 p.s.i. until no more hydrogen was
taken up.
200 ml. of methanol (prepared by distilling over sodium
hydroxide or directly over magnesium methoxide) is
purged four times with nitrogen. The flow of nitrogen
is maintained, the suspension is heated to 60° C. with
stirring, and 0.675 g. (12.5 millimols) of solid sodium
The 5.0 g. of solid 3-ethylenedi0xy-A5-preg
nene - 170:,21 - diol-11,20-dione
21-dibenzylphosphate is
added and the reduction is continued until two additional
equivalents of hydrogen are absorbed. The reduction is
stopped, the catalyst is ?ltered 01f, and the resulting so
lution is evaporated in vacuo to about 40 ml. The mix
ture, containing some crystalline material, is cooled to
methoxide is added all at once. The nitrogen flow, heat
ing, and stirring are continued until the solution is homo
0° C., and the crystalline 3-ethlenedioxy-A5-pregnene—
geneous (5 to 7 minutes), whereupon the heat is re 60
17a,21-diol-11,20-dione 21-phosphate, N-methylmorpho
moved and the mixture was rapidly cooled 10-15 ° C.
line salt is collected, washed with ethanol, then with ether,
The solution is acidi?ed with 0.85 ml. of glacial acetic
and air dried. Yield 3.3 g., M.P. 195-210“ C.
acid (13.5 millimols), diluted with 100 ml. of water, and
concentrated in vacuo to 200 ml. An additional 100 ml.
of water is added, and the concentration is continued to 65
a ?nal volume of 150 ml. The resulting slurry is cooled
in ice, and the solid is collected, washed with water, and
dried in air. Recrystallization from ethyl acetate yields
substantially pure 3-ethylenedioxy-A5-pregnene-17a,21
diol-l1,20-dione, M.P. 198~200° C.
EXAMPLE 18
3i-Ethylenedioxy-A5-Pregnene-l 7oi,21 -Di0l-1 1 ,ZO-Dione
EXAMPLE 22
Sodium Salt of Cortisone 21 -Ph0sphate
Ten grams of 3-ethylenedioxy-A5-pregnene-17u,21-dio1
11,20-dione 21-phosphate, Nrmethylmorpholine salt are
70 dissolved in 500 ml. of methanol and 20 g. of Amberlite
IRC-120 (hydrogen cycle) is added. The mixture is
shaken overnight (16-20 hours) and then the resin is
removed. The solution containing cortisone phosphate
is treated with 2.5 g. of sodium bicarbonate (2 equiva
ZI-Methanesulfonate
A solution of 24.5 g. (0.06 mol) of 3-ethylenedioxy 75 lents) in 5 ml. water and then evaporated to 5 ml. at
3,068,223‘
13
14
25° C. The residue is taken up in 100 ml. of water; this
7. The process which comprises reacting a compound
aqueous solution is extracted with ethyl acetate and ether,
and then lyophilized. The resultant solid is taken up in
100 ml. of methanol, the solution is ?ltered, and the
amorphous sodium salt of cortisone phosphate is precip
itated with 200 ml. of ether. This material is collected,
washed with ether and petroleum ether, and then dried
in air. Yield 6.0 g., max. 238, E% 290, [(111325 +145“
having the formula
CH OSOB 2
r2
2
(c.=1, methanol).
Various changes and modi?cations may be made in 10
carrying out the present invention with departing from
the spirit and scope thereof. Insofar as these changes
and modi?cations are within the scope of the appended
claims, they are to be considered as part of this invention.
We claim:
1. A compound having the general formula
“ wherein R2 is a lower alkyl group with an iodide salt to
form the corresponding 21-iodo compound,
8. The process which comprises reacting a compound
2
having the formula
H
(3H2- o- 1% cougar’ ) 2
(EH2 oso 2R2
25
30
wherein R2 is a lower alkyl group with an iodide salt to
wherein R is a substituent selected from the group con
form the corresponding 2l-i0do compound.
9. The process which comprises reacting 3-ethylene
sisting of keto and ,B—hydroxy, and R3 is a phenyl group.
2. S-ethylenedioXy-A5-pregnene - 170:,21 - diol - 11,20
dioXy-M-pregnene-l118-17a,2l-triol-20-one-21 - methane~
dione Zl-dibenzylphosphate.
sulfonate with sodium iodide to form 3-ethylenedioXy-2L
3. A compound having the general formula
iodO-M-pregnene-l1[3,l7a-diol-20~one.
10. The process which comprises reacting 3-ethylene
diOXY-Z1-lOdO—A5—pr6gI1en8—1113,17oc-di0l-20-0I1E with sil
ver dibenzylphosphate to form 3-ethylenedioxy-A5-preg
nene-llB,l7a,21-triol-20-one Zl-dibenzylphosphate.
11. The process which comprises hydrogenating a
compound having the formula
0
45
wherein R is a substituent selected from the group con
sisting of keto and ,B-hydroxy, and R4 is a tertiary amine.
4. N~methylmorpholine salt of S-ethylenedioxy-Ai
pregnene-17e,2l-diol-11,20—dione 21-pl‘osphate.
5. A compound having the general formula
wherein R3 is a phenyl group in the presence of a hydro
genating catalyst and a tertiary amine to form the cor
responding tertiary amine salt of 3-ethylenedioXy-A5
60
pregnene-l7a,21-diol~11,20-dione-21-phosphate.
12. The process which comprises hydrogenating a com
pound having the formula
(i5
wherein R is a substituent selected from the group con
sisting of keto and ?—hydroxy, and R3 is a phenyl group.
6. A4-pregnene-17e,2l-diol-3,l1,2(l-trione 2l-dibenzyl
phosphate.
75
3,068,223
15
16
11i3’,17a,21-triol-3,20-dione
wherein R3 is a phenyl group in the presence of a hydro
genating catalyst and a tertiary amine to form the cor
ZI-methanesulfonate
With
sodium iodide to form 21-iodo-A‘1-pregnene-115,17a-diol
3,20-dione.
15. The process which comprises reacting 21-iodo-A4
pregnene-l'iu-ol-ll1,20—tri0ne with silver dibenzylphos
responding tertiary amine salt of 3-ethylenedioXy-A5-preg
none-1 113,17¢,21-triol-20—one-2l-phosphate.
13. The process which comprises reacting a compound
having the formula
phate to form A4-pregnene-17m,21-diol-3,11,2O-trione
21~dibenzylphosphate
16. The process Which comprises reacting 21-iod0-A4
pregnene-l1B,17a-diol-3,20-di0ne with silver dibenzyl
10
phosphate to form A4-pregnene-11,8,17a,21-tri0l13,20
cliche-21-dibenzylphosphate.
References Cited in the ?le of this patent
UNITED STATES PATENTS
o
wherein R is selected from the group consisting of keto
and ,B-‘hydroxy and R2 is a lower alkyl group with an
iodide salt to form the corresponding 21-iodo compound.
14. The process which comprises reacting M-pregnene
2,668,816
2,684,968
2,713,587
2,779,775
2,842,568
2,870,177
Miescher et al. __________ __ Feb. 9,
Bergstrom ____________ __ July 27,
Bergstrom ____________ __ July 19,
Sarett ________________ __ Jan. 29,
Herz et a1. ____________ -_ July 8,
Conbere et al __________ __ Ian. 20,
1954
1954
1955
1957
1958
1959
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